Unveiling Palmitoyl Thymidine Derivatives as Antimicrobial/Antiviral Inhibitors: Synthesis, Molecular Docking, Dynamic Simulations, ADMET, and Assessment of Protein–Ligand Interactions
Abstract
1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Characterization
2.3. Antibacterial Potential
2.4. MIC and MBC Evaluation
2.5. Antifungal Susceptibility
2.6. SAR Assessment
- ✓
- The potential implications for long-chain aliphatic hydrocarbons (lauroyl, myristoyl);
- ✓
- The binding acquaintances are enhanced by the attachment of the palmitoyl-substituted acyl group at position 5′;
- ✓
- By combining the acyl groups that are substituted at position 3′ with the lauroyl and myristoyl groups, the binding affinity is increased;
- ✓
- The presence of pyrimidine and ribose rings is also important for the efficacy of the activity.
2.7. Optimized Structures and MEP
2.8. Frontier Molecular Orbital (FMO)
2.9. Global Reactivity Parameters
2.10. 3D-NBO Charge
2.11. Molecular Docking Pose and Interaction Analysis of the Monkeypox Virus
2.12. Molecular Docking Pose and Interaction Analysis of the Marburg Virus
2.13. ADMET Prediction
2.14. MD Trajectory Data Analysis of Monkeypox (Mpox) Virus
2.14.1. RMSD Analysis
2.14.2. RMSF Analysis
2.14.3. Radius of Gyration (Rg) Analysis
2.14.4. Solvent Accessible Surface Area (SASA)
2.15. Assessment of Protein–Ligand Interactions
2.16. MD Trajectory Data Analysis of Marburg Virus
2.16.1. RMSD Analysis
2.16.2. RMSF Analysis
2.16.3. The Radius of Gyration (rGyr) Analysis
2.16.4. Solvent Accessible Surface Area (SASA)
2.17. Protein–Ligand Contact Analysis
3. Materials and Methods
3.1. Materials, Samples, and Equipment
3.2. Synthesis
3.2.1. The 5′-O-(Palmitoyl)thymidine (2)
3.2.2. The General Procedure for the Preparation of Palmitoyl Derivatives (3–6)
5′-O-Palmitoyl-3′-O-(pivaloyl)thymidine (3)
3.2.3. The 3′-O-Lauroyl-5′-O-(palmitoyl)thymidine (4)
3.2.4. The 3′-O-Myristoyl-5′-O-(palmitoyl)thymidine (5)
3.2.5. The 3′-O-(4-t-Butylbenzoyl)-5′-O-(palmitoyl)thymidine (6)
3.3. In Vitro Antibacterial Activity Test
3.4. Determination of the MIC and MBC via the Broth Microdilution Method
3.5. Determination of Mycelial Growth
3.6. Structure–Activity Relationship
3.7. Computational Details
3.8. Protein Selection and Molecular Docking
3.9. ADMET Properties Involving Pharmacokinetic Prediction
3.10. Molecular Dynamics Simulation
4. Conclusions and Future Perspectives
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ADMET | absorption, distribution, metabolism, excretion, and toxicity |
DFT | density functional theory |
FMO | frontier molecular orbital |
HOMO | highest occupied molecular orbital |
LUMO | lowest unoccupied molecular orbital |
MBC | minimum bactericidal concentration |
MD | molecular dynamics |
MEP | molecular electrostatic potential |
MIC | minimum inhibitory concentration |
NBO | natural bond charge |
PASS | prediction of substance activity spectra |
SAR | structure–activity relationship |
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Diameter of Inhibition Zone (mm) | |||||
---|---|---|---|---|---|
Entry | B. subtilis (+ve) | B. cereus (+ve) | E. coli (−ve) | S. typhi (−ve) | P. aeruginosa (−ve) |
1 | NI | NI | NI | NI | NI |
2 | NI | NI | 7.84 ± 0.1 | NI | NI |
3 | NI | NI | 7.75 ± 0.2 | NI | NI |
4 | * 11.00 ± 0.1 | * 17.00 ± 0.4 | * 20.75 ± 0.2 | 9.75 ± 0.2 | * 17.75 ± 0.2 |
5 | * 10.00 ± 0.2 | * 15.00 ± 0.2 | 9.26 ± 0.2 | 8.13 ± 0.3 | * 14.00 ± 0.1 |
6 | NI | NI | NI | NI | NI |
Azithromycin | 18.25 ± 0.3 ** | 17.75 ± 0.3 ** | ** 17.25 ± 0.1 | ** 18.00 ± 0.2 | ** 18.5 ± 0.3 |
Entry | % Fungal Mycelial Growth Inhibition in mm (20 μg/μL) | |
---|---|---|
Aspergillus niger | Aspergillusflavus | |
1 | NI | NI |
2 | * 73.72 ± 1.2 | * 77.45 ± 1.0 |
3 | * 77.54 ± 1.1 | NI |
4 | * 64.40 ± 1.3 | * 74.59 ± 1.2 |
5 | 55.61 ± 1.1 | * 61.52 ± 1.0 |
6 | NI | NI |
Nystatin | ** 65.4 ± 1.0 | ** 64.1 ± 1.0 |
HOMO | LUMO | (eV) | η (eV) | μ (eV) | ω (eV) | ||
---|---|---|---|---|---|---|---|
1 | −6.83 | −1.52 | 4.17 | 2.65 | 0.37 | −4.17 | 3.28 |
2 | −6.64 | −1.33 | 3.98 | 2.65 | 0.37 | −3.98 | 2.98 |
3 | −6.60 | −1.27 | 3.93 | 2.66 | 0.37 | −3.93 | 2.90 |
4 | −7.25 | −1.84 | 4.54 | 2.70 | 0.37 | −4.54 | 3.81 |
5 | −6.67 | −1.34 | 4.00 | 2.66 | 0.37 | −4.00 | 3.00 |
6 | −6.73 | −2.05 | 4.39 | 2.34 | 0.42 | −4.39 | 4.11 |
Ligand | Binding Affinity (kcal/mol) | Number of H-Bonds Formed |
---|---|---|
1 | −4.5 | 0 |
2 | −4.6 | 1 |
3 | −5.1 | 1 |
4 | −5.0 | 1 |
5 | −6.2 | 2 |
6 | −5.7 | 1 |
Reference (acyclovir) | −4.2 | 2 |
Ligand | Binding Affinity (kcal/mol) | Number of H-Bonds Formed |
---|---|---|
1 | −4.9 | 1 |
2 | −5.3 | 1 |
3 | −5.5 | 1 |
4 | −5.3 | 1 |
5 | −5.6 | 2 |
6 | −7.0 | 3 |
Reference (acyclovir) | −4.3 | 1 |
2 | 3 | 4 | 5 | 6 | |
---|---|---|---|---|---|
Water solubility (log mol/L) | −5.061 | −2.892 | −5.4 | −3.597 | −2.892 |
Caco-2 permeability (log Papp in 10−6 cm/s) | 0.53 | 3.008 | 0.703 | 0.185 | 3.008 |
Intestinal absorption (% Absorbed) | 68.559 | 69.881 | 77.117 | 71.954 | 69.881 |
Skin permeability (log Kp) | −2.767 | −2.735 | −2.714 | −2.735 | −2.735 |
VDss (log L/kg) | −0.732 | 0.011 | −0.738 | −1.203 | 0.011 |
Fraction unbound (Fu) | 0.137 | 0.381 | 0 | 0.089 | 0.381 |
BBB permeability (log BB) | −1.283 | −0.245 | −1.254 | −1.784 | −0.245 |
CNS permeability (log PS) | −3.409 | −1.488 | −2.85 | −3.782 | −1.488 |
CYP2D6 substrate | No | No | No | No | No |
CYP3A4 substrate | Yes | No | Yes | Yes | No |
CYP1A2 inhibitor | No | Yes | No | No | Yes |
CYP2C19 inhibitor | No | No | No | No | No |
CYP2C9 inhibitor | No | No | No | No | No |
CYP2D6 inhibitor | No | No | No | No | No |
CYP3A4 inhibitor | No | No | No | No | No |
Renal OCT2 substrate | No | No | No | No | No |
AMES toxicity | No | Yes | No | No | Yes |
Max. tolerated dose (log mg/kg/day) | −0.2 | 0.438 | 0.069 | 0.168 | 0.438 |
Hepatotoxicity | Yes | No | Yes | Yes | No |
hERG I inhibitor | No | No | No | No | No |
hERG II inhibitor | No | No | No | No | No |
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Kawsar, S.M.A.; Al-mijalli, S.H.; Bouzid, G.; Abdallah, E.M.; Siddiquee, N.H.; Hosen, M.A.; Horchani, M.; Ghalla, H.; B. Jannet, H.; Fujii, Y.; et al. Unveiling Palmitoyl Thymidine Derivatives as Antimicrobial/Antiviral Inhibitors: Synthesis, Molecular Docking, Dynamic Simulations, ADMET, and Assessment of Protein–Ligand Interactions. Pharmaceuticals 2025, 18, 806. https://doi.org/10.3390/ph18060806
Kawsar SMA, Al-mijalli SH, Bouzid G, Abdallah EM, Siddiquee NH, Hosen MA, Horchani M, Ghalla H, B. Jannet H, Fujii Y, et al. Unveiling Palmitoyl Thymidine Derivatives as Antimicrobial/Antiviral Inhibitors: Synthesis, Molecular Docking, Dynamic Simulations, ADMET, and Assessment of Protein–Ligand Interactions. Pharmaceuticals. 2025; 18(6):806. https://doi.org/10.3390/ph18060806
Chicago/Turabian StyleKawsar, Sarkar M. A., Samiah Hamad Al-mijalli, Gassoumi Bouzid, Emad M. Abdallah, Noimul H. Siddiquee, Mohammed A. Hosen, Mabrouk Horchani, Houcine Ghalla, Hichem B. Jannet, Yuki Fujii, and et al. 2025. "Unveiling Palmitoyl Thymidine Derivatives as Antimicrobial/Antiviral Inhibitors: Synthesis, Molecular Docking, Dynamic Simulations, ADMET, and Assessment of Protein–Ligand Interactions" Pharmaceuticals 18, no. 6: 806. https://doi.org/10.3390/ph18060806
APA StyleKawsar, S. M. A., Al-mijalli, S. H., Bouzid, G., Abdallah, E. M., Siddiquee, N. H., Hosen, M. A., Horchani, M., Ghalla, H., B. Jannet, H., Fujii, Y., & Ozeki, Y. (2025). Unveiling Palmitoyl Thymidine Derivatives as Antimicrobial/Antiviral Inhibitors: Synthesis, Molecular Docking, Dynamic Simulations, ADMET, and Assessment of Protein–Ligand Interactions. Pharmaceuticals, 18(6), 806. https://doi.org/10.3390/ph18060806